SA515361104B1 - Pyridin-4-yl derivatives - Google Patents

Abstract

The invention relates to compounds of the Formula (I), Formula (I) wherein R1 and R2 are as described in the description, their preparation and their use as pharmaceutically active compounds. Said compounds particularly act as immunomodulating agents.

Description

— \ — Em-Pyridin—4-yl derivatives FULL DESCRIPTION BACKGROUND The present invention relates to receptor agonists 510/061 of Formula (1) and their use as Jd dlldingredients preparation preparation of pharmaceutical compositions The invention further relates to related aspects which © 0710065585 comprise processes for preparing compounds ccompounds Pharmaceutical compositions containing the compound of formula (a); And using them as compounds that improve vascular function and as immunomodulating agents, either alone or in combination with other active compounds or therapies General description of the invention Vo The human immune system is designed to defend About the body ua body External micro-organisms and substances that cause infection or disease (disease) Complex regulatory mechanisms ensure that the immune response is Targeted against the intruding substance or organism rather than against -host Jilall and in YO in some cases these reference organisms have unregulated control mechanisms and can develop autoimmune responses. The result of the uncontrolled inflammatory response is in the severe organ hall cell tissue tissue or joint damage and with concurrent treatment; The overall immune system is suppressed and the body's ability to react to infection is severely compromised as well. Typical drugs in A

AA contains azathioprine 82811007006 chlorambucil cyclophosphamide cyclosporin or methotrexate Corticosteroids that reduce inflammation and suppress the immune response can cause side effects when used In long-term treatment © 009a. Nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce pain 7 and inflammation; However, it does show significant side effects. Alternative therapies include agents that activate or inhibit cytokine signaling. Orally active compounds with immunomodulating properties may improve 0 without compromising immune responses and with significantly reduced side effects. Current treatments for inflammatory diseases Uncontrolled. In the field of organ transplantation, the immune response to the pial rejection Au must be suppressed. And certain Ail transplant recipients can succumb to the sale receptors even when they take immunosuppressive drugs Lelie 0 00095. Rejection occurs more frequently in the first few weeks after transplantation but remission episodes can occur. La rejection episodes after months or even years of transplantation. Combinations of three or four medications are commonly used to provide maximum protection against rejection while minimizing side effects. Current standard drugs used to treat transplant rejection interfere with the discrete intracellular pathways in activating type 1 or type 8 white blood cells. Examples of such drugs are Cyclosporine 0117M0105/A0; daclizumab, basiliximab, everolimus or 6+, which interfere with coytokine release or signaling; azathioprine; or leflunomide, which inhibits nucleotide synthesis, or - deoxy-Yo spergualin (d5-deoxyspergualin, an inhibitor of WIA leukocyte differentiation Y .£4

The OEY that is useful for immunosuppressive therapies broadly affects its effects, but the generalized immunosuppression produced by these drugs reduces the immune system's defense against infection and malignancies (Lady malignancies). Typical immunosuppressive drugs are often used in high dosages. and can cause or accelerate organ damage. Strong and long-lasting immune modulator, which is achieved by reducing the number of circulating and infiltrating T- and B-lymphocytes without affecting their maturation 0 102100 02 memory or expansion 6*»0805101. Reduction of Talal and Circle 8 cells as a result of the receptor 510,/50061 assistance; Lay in connection with the observed movement of endothelial cell layer function associated with activation of the 510,/21061 receptor; These compounds are useful in the treatment of uncontrolled inflammatory diseases and the improvement of Oza r vascular. IDF 1797971/7008 (Document A) discloses compounds that act as receptor adjuvants 1 510/061 and exhibit the immunomodulatory effect as described above. On the other hand; Multiple reports indicate that activation of the SIP receptor is associated with Vaso- and bronchial vasoconstriction (Salomone et al.

Brit.

J.

Pharmacol. 153 (2008) Sie) bronchoconstriction, Murakami et al.

Mol.

Pharmacol. 77 (2010) 704-713; Luck et al. 140-147 (al.

Cellular Physiology and Biochemistry 26 (2010) 87-96 Increased blood pressure Y. (eg €52,985 (2012) 7 (Fryer et al.

PLOS One lowers heart rate (eg 3154 (2010) 53 Hamada et. al.

J.

Med.

Chem. 8) and pulmonary epithelial leakage (eg Gon et al. 9270-9275 (2005) 102 7/0/45). Hence selectivity against the SIP receptor is an advantage of a particular SIP receptor cofactor (Hale et al.

Bioorg.

Med.

Chem.

Lett. 14 Si veo 3501-3505 (2004)(-

-H-

unexpectedly; It has been discovered that the compounds of the present invention have reduced receptor activity

and 51 when compared with the closest analogs detected in Document A. And this becomes clear

From the data noted in Table 1 and Table oF the compound of Example 1 of the present invention is illustrated;

For example; 0m562 to 4400 nano SIP; Jai NM se while showing the nearest isotope in

0 Document a ov Jud) of document a) the ECs value of a nanomolar Vote. Similarly; be composite

Example ¥ is clearly Ji efficient on the SIP receiver; when compared with the closest detected counterpart in

Document A (Example 011 of Document A). also; Example 5 of the present invention is considerably less efficient

on the SIP receiver; when compared with its counterpart of the A document (S—enantiomer of racemates

600156 Example YY of Document A) The same is true for compounds of Examples 1 and A and isotopes

0 corresponds to Document A (Example Yee and Example 777; respectively for Document A). Table 1: instead of 1 8 = N 0 b l in sense on J: Na EE Eq. y

No no no table? 0 \_/ = N 9 ° for the [3 oH test

Rit counterpart in of

Yori. LY (example 57 | ethyl 1 for example I sq 8 " " Juan [ 011 for example ? (example for i lr

YY 1 (5-Isomorph | Isobutyl 5 Jal Example YY from Document (I for Example 7 Yet Jad) | Bent-3?-YL 5 T TT for Example YYY JEAN) A | Cyclopentyl oY 3 I by taking cles the data presented in Table 1 and Y show that it is related to lower activity at the STP receptor; the pyridine derivatives of the present invention are better than the 7 analogues. Irrespective of the nature of the R! substituent of the compounds of formula (a) of the present invention, the compounds of the present invention may be employed alone or in combination with Typical drugs that inhibit a

—y— activate cell 7; To provide a novel immunomodulatory therapy with a reduced susceptibility to infection when compared with standard immunosuppressive therapy. also; The compounds of the present invention can be used in combination with low doses of conventional immunosuppressive therapies to provide, on the one hand, “effective immunomodulatory activity” while on the other hand reducing the peripheral organ damage associated with higher doses of typical drugs. Monitoring enhanced epithelial cell layer function associated with activation of the Lelie suppressor © 515/5061 receptor provides traditional advantages of compounds for improving vascular function. An amino acid and nucleotide sequence are the most well-known human nucleotide sequences in the field. 510 /1061 and 510/0063 for 686 receivers

Hla, T., and Maciag, T., J. Biol Chem. 265 (1990), 9308- and is published on 11 of WO 99/46277 ©0991 Oct 117 of 9313; WO 91/15583 0 , Tokuda M., Hatase O., Brenner S., Biochem. Yamaguchi 1 934 Sep Biophys. Res. Communicate. 227 (1996), 608-614,

An S., Bleu T., Huang W., Hallmark O.G., Coughlin S.R., Goetzl E.J., efficacy and potency are evaluated by FEBS Left. 417 (1997), 279-282 and by measuring lymphocytes ECyp to determine the values of GTPYS compounds of formula (1) using the Vo oral test in rats after oral administration (experimental). respectively (see the experimental part cadministration in the first embodiment; the invention relates to a compound of formula (a); (i

R1 P7 >>

ANN R2 on (I) form 0 bonded carbon atom; Preferably where the carbon atom carries GC, s—alkyl alkyl RY representing gay

“A” cyclopentyl at least one hydrogen; or cyclopentyl 3,3 pyridine ring with a pyridine ring and ~OCH,~CH(OH)-CH,-NHCO-CH,0OH (fis R? —n ethyl ethyl RY) where oi Another embodiment of the invention relates to a compound of the form (ii dsobutyl n-butyl lithoeb-0 isopropyl isopropyl n-propyl cyclopentyl or cyclopentyl pent=3-yl pent- ?-yl dsopentyl isopentyl Wun RUS where oi of the invention relates to a compound of form AT (i isopropyl; isobutyl or cyclopentyl. of form a); aay of the invention relates to a compound HAT relates to an embodiment (iV where A is cyclopentyl. 011)0a00- in R? for stereocenter group 5. Formation of branched alkyl groups with a saturated chain; branched or straight Cy 5 means an alkyl term with two to five carbon atoms. straight chain alkyl groups yo or non-stereogenic compounds of formula (1) can contain one or more centers and one or more asymmetric carbon atoms. Ji can exist Compounds of formula (1) are casymmetric or preferably pure stereoisomers as mixtures of stereoisomers. Mixtures of stereoisomers can be separated in a method known to a person skilled in this field. pure Pharmaceutical formulations; diseases and the like; SY where the plural form of compounds is used; 0 This is intended to also mean a monomeric compound; salt or the like. Any reference before or hereinafter to a compound of formula (1) shall be understood as referring to the salts; in the proper and proper form ol) of the compound of formula Lana and in particular the acceptable salts. "pharmaceutically acceptable salts Zou!" ,

Inorganic, organic and/or base addition salts based on the presence of basic and/or acidic groups. in the subject compound. For reference, see, for example, "Handbook of Pharmaceutical Salts."

Properties, Selection and Use.’, P.

Heinrich Stahl, Camille G.

Wermuth (Eds.), Wiley-VCH, 2008 and 'Pharmaceutical Salts and Co-crystals', Johan Wouters and Luc Quéré (Eds.), RSC o Publishing, 2012. The present invention also includes isotope-numbered compounds. disotopically special numbered H' (deuterium of formula ol) These compounds are identical to compounds of formula A except that one or more of the atoms has been replaced by an atom that has the same atomic number but 0 has an atomic mass different from the atomic mass normally found in nature. Hence isotopic-numbered compounds. Especially H-numbered (deuterium) of formula (1) and their salts are within the scope of the present invention. Substitution of hydrogen by the heavier isotope can PH (deuterome) leads to ST metabolic stability leading to Sie mid-Wie half-life je in body all 7/70 77 or lower dose requirements; or can of lead to inhibition Low inhibition of VO 0450 of cytochrome P450 enzymes leading to an improved safety profile.In one embodiment of the invention, the compounds of formula (A) are not isotopic numbered. ; Or they are only numbered with one or more deuterium atoms. In the subform, compounds of formula A are not isotopic numbered at all. The isotopic compounds of formula (a) may be prepared in analogy to the methods described below; But using the appropriate isotopic change of the reagents | 0 appropriate or starting materials. Examples of pyridine compounds are selected according to formula (1) of: (5)-l!-(?-) 7-egel = -(e-) 7-ethylpyridine-; (dr 7, © -oxadiazole -?- yl)-7-methyl Y= (mS si-hydroxypropyl)-7-hydroxyacetamide -4-(2-81)-3)-11-(5) (5—(2-ethylpyridin—4-yl) )-1,2,4-oxadiazol-3-yl)-6-methyl-phenoxy)-2- (hydroxypropyl)-2-hydroxyacetamide + Ji (Y)-Y)-N=(S) = - (©-(7-propylpyridine-;-yl)-0,7?-oxadiazole (dr Y= == gay ym methyl-phenoxy)-?-hydroxypropyl)-7-hydroxyacetamide - 4-un2-81)-3)-11-(5)‎ (5-(2-propylpyridin-4-yl)-1,2,4-oxadiazol-3-yl)-6-methyl-phenoxy)-2 - thydroxypropyl)-2-hydroxyacetamide (5)-1-(7-(7-equil-;-(©-(7-isopropylpyridine-;-yl)-1,7,4-oxadiazole-?-) 8(-11-)3-2-yl)-7-methylphenoxy)-?"-hydroxypropyl)-7-hydroxyacetamide © ethyl-4—(5—(2-isopropylpyridin-4-yl)-1, 2,4-oxadiazol-3-yl)-6- ¢tmethylphenoxy)-2-hydroxypropyl)-2-hydroxyacetamide ?-oxadiazol-?-yl)-7-17 NV (dr(5)-l!- (?-( 7-ethyl = -(e-( 7-butylpyridine-;methylphenoxy)-7-hydroxyprop yl)-7-hydroxyacetamide-4-alan (2-81)-3)-11-(5)(5-(2-butylpyridin-4-yl)-1,2,4-oxadiazol-3-yl)- 6-methylphenoxy)-2- 0 hydroxypropyl)-2-hydroxyacetamide pyridine-; -yl)-1, 7, 4-oxadiazole -?- Os sal Y)=0)= (5)-1-(7-(7-ioqyl-;)9(-1-)3- (2-yl)-7-methylphenoxy)-7-hydroxypropyl)-7-hydroxyacetamide ethyl-4—(5-(2-isobutylpyridin-4-yl)-1,2,4-oxadiazol-3-yl )-6- ¢tmethylphenoxy)-2-hydroxypropyl)-2-hydroxyacetamide 0 (5)-1-(7-(7-equil-;-(© -(7-isopentylpyridine-;-yl)-1, 7, 4-oxadiazole-?-yl)-7-methylphenoxy)-7-hydroxypropyl)-? -Hydroxyacetamide-Al-2-81)-3)-11-(5)4-(5-(2-isopentylpyridin-4-yl)-1,2,4-oxadiazol-3-yl)-6- ¢tmethylphenoxy )-2-hydroxypropyl)-2-hydroxyacetamide -pyridine -; -yl)-0, “, ;-oxadiazole-?-(dr 1 - -ethyl = -(E -( 7-pentane Y)-Y)-N-(S) 0 (9(-1-) (3-)2-yl)-7-methylphenoxy)-7-hydroxypropyl)-7-hydroxyacetamide ethyl-4-(5-(2—(pentan-3-yl)-pyridin—4-yl)- 1,2,4-oxadiazol-3-yl)-6- ¢methylphenoxy)-2-hydroxypropyl)-2-hydroxyacetamide (5)-L-1-(7-(7-ethyl-;-(5-) (7-pentylcyclopyridine-;-yl)-01, 7, ;-oxadiazole-?-phenoxy)-7-hydroxy-propyl)-7-hydroxyacetamide-2)-3)-11-(8) lythym-)ly Yo ethyl-4—(5-(2-cyclopentylpyridin-4-yl)-1,2,4-oxadiazol-3-yl)-6- gay

-11- .methylphenoxy)-2-hydroxypropyl)-2-hydroxyacetamide Compounds of formula (1) and their pharmaceutically acceptable salts may be used as drugs, for example in the form of formulations or (particularly oral Sie) enteral through the abdomen Pharmaceutical administration for topical application or inhalation including topical use Wy) parenteral parenteral of prevention and appropriate in decreasing the number of circulating lymphocytes and prophylactic ¢(inhalation©) associated with activated immune system disorders. and/or treat diseases or disorders The production of pharmaceutical formulations can be carried out in a manner that will be familiar to any experienced person.

Remington, 7/76 Science and Practice of this field (see eg

Pharmacy, 21st Edition (2005), Part 5, “Pharmaceutical Manufacturing “by Presentation of Prescribed Compounds” ([published by Lippincott Williams & Wilkins]) 0 andl of Formula (1) or its pharmaceutically acceptable salts; optionally in combination with substances of value along with appropriate carriers; non-toxic 000-106 galenical inert in form of administration adjuvants; pharmaceutically acceptable solid or liquid and in desired form; ordinary 4” pharmaceutical adjuvants. The compound of Formula (1) is useful in the prevention and/or treatment of (1) diseases or disorders associated with an activated immune system. Those diseases or disorders related to an activated immune system are selected and prevented/treated with compounds from Formula (A) For example from the group consisting of transplant rejection of organs, transplanted tissues; graft-versus—host or cells; grafting-versus-host diseases including autoimmune syndromes daly Ye. systemic lupus erythematosus systemic lupus erythematosus carthritis ¢Hashi moto's thyroiditis Hashimoto's thyroid gland ¢cantiphospholipid syndrome cpg, multiple sclerosis dlymphocytic thyroiditis uveitis type | diabetes Type 1 diabetes tmyasthenia gravis ala muscular Kawasaki disease ¢ scleritis cepiscleritis cuveitis Yo posterior; Posterior uveo-retinitis (Kawasaki's disease)

“yy uveitis Uveitis associated with Behcet’s disease Symptoms of uveitis and meningitis cuveomeningitis syndrome allergic encephalomyelitis allergic tencephalomyelitis chronic allograft vasculopathy ¢ chronic allograft vasculopathy immune diseases post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis—tinfectious glomerulonephritis inflammatory and hyperproliferative arthritis hyperproliferative skin diseases Psoriasis ¢psoriasis psoriatic arthritis ¢psoriatic arthritis atopic dermatitis ¢psoriatic arthritis myopathy dermatitis 6M810; Gill muscles myositis: no0070081;_ dermatitis ula als dull_ costeomyelitis 0] 600186;_ eczematous dermatitis 6026081005; als seborrheic dermatitis lichen planus pemphigus pemphigoid 5na0ana0; Epidermolysis bullosa 501058 ¢epidermolysis urticaria dad, cwurticaria neurovascular cangioedema vasculitis erythema cerythema cutaneous eosinophilia ccutaneous eosinophilia Yo acne ©800; scleroderma ¢scleroderma calopecia areata keratoconjunctivitis tkeratoconjunctivitis ¢vernal conjunctivitis keratitis herpetic keratoconjunctivitis [75 ©”); ¢dystrophia epithelialis corneae corneal opacity 38;tocular pemphigus eMooren's ulcer Graves' phi scleritis 501601005; Ulcerative keratitis ophthalmopathy 0

Vogt-Koyanagi-Harada Management of symptoms of Vogt Koyanagi tophthalmopathy ¢ pollen allergies sarcoidosis sarcoid ¢ syndrome bronchial asthma reversible obstructive airway disease reversible obstructive airways asthma tintrinsic asthma autoimmune asthma ¢ intrinsic asthma 161016l8; Allergic asthma 328 Yo extrinsic extrinsic asthma dust asthma ¢dust asthma chronic or inveterate asthma alias and airway hyperresponsiveness late asthma

1h

cand airway hyper-responsiveness ¢ bronchiolitis bronchitis

Bronchitis Endometriosis Endometriosis Orchitis Stomach ulcers Tgastric ulcers Ischemic bowel diseases Diseases

Al enterocolitis ll <inflammatory bowel diseases intestinal lesions intestinal lesions associated with thermal burns ¢ necrotizing enterocolitis © ccoliac disease tassociated with thermal burns

rectum proctitis ¢ eosinophilic gastroenteritis 35S ceosinophilic gastroenteritis mast cells tmastocytosis Crohn's disease ulcerative colitis vascular damage caused by cerebrovascular disease

ischemic diseases AD and thrombosis ¢thrombosis atherosclerosis ¢fatty heart ¢fatty heart myocarditis ¢myocarditis myocardial infarction cardiac 1]8000; Caortitis syndrome is a general malaise with emaciation due to

vascular jas ¢cachexia due to viral disease teczema eczema rhinitis migraine thrombosis

15 - interstitial nephritis PEGAG 8-10000660 induced nephropathy ¢ nephropathy Goodpasture's syndrome ¢ Goodpasture's syndrome Symptoms of all chemolytic-uremic syndrome Diabetic nephropathy ¢ nephropathy glomerulosclerosis ¢ glomerulosclerosis glomerulonephritis ¢ glomerulonephritis ¢ tubulointerstitial nephritis

Yo interstitial cystitis multiple myositis Guillain-Barré syndrome ¢Guillain—Barré syndrome Meniere's disease ¢polyneuritis emultiple neuritis spinal cord inflammation ; mononeuritis 10000605; ¢radiculopathy sae activity

Hyperthyroidism thyperthyroidism Bazdov's disease 885600175; Thyrotoxicosis

cthyrotoxicosis© WIA pure red cell aplasia; aplastic anemia 000185116/a; purpura

a

-1?-

thrombocytopenic purpura 101008116; autoimmune hemolytic anemia autoimmune platelets thrombocytopenia 801010007106; Agranulocytosis ¢cagranulocytosis ¢pernicious anemia ¢megaloblastic anemia

0 Erythrocytes Lilia canerythroplasia Bone costeoporosis Fibrous lung tumor 9 Interstitial pneumonia of unknown cause Tidiopathic interstitial pneumonia Dermatomyositis Tdermatomyositis Common acquired condition Tleukoderma vulgaris Ichthyosis vulgaris 100157 /055; photosensitivity photoallergic ¢sensitivity T-cell lymphoma cutaneous tcutaneous T cell lymphoma 0 - polyarteritis nodosa ¢polyarteritis nodosa acute Huntington's chorea 8 ¢Sydenham's chorea Lac's disease Emyocardosis Myocarditis Emyocarditis Scleroderma ¢scleroderma Wegener's tgranuloma Sjogren's syndrome Obesity cadiposis ¢eosinophilic fascitis Lesions Gums Lesions of gingiva Periodontium Yo alveolar bone calveolar bone 055868 substantia 5 male pattern alopecia or talopecia 05 muscular dystrophy 87a0a00150 pyoderma ¢Sezary's syndrome thypophysitis chronic adrenal insufficiency tAddison's disease yo's injury ischemia-reperfusion injury of organs that happen on D Prevention ¢preservation endotoxin shock cendotoxin shock epseudomembranous colitis colitis colitis caused by drugs or radiation radiation ischemic acute renal failure ¢insufficiency cchronic renal insufficiency lung cancer ‎lung ‎Yo +©02800; malignancy of lymphoid origin or chronic lymphocytic leukemias 016a20; Lymphoma

a

“yoo .tcataracta cataracts ¢pulmonary emphysema 4) swelling <ymphoma macular atrophy retinitis pigmentosa retinitis pigmentosa esiderosis eye mourning burn vitreal scarring vitreous cavity ¢senile macular degeneration tychoidal dermatitis erythema corneal alkali burn ccement dermatitis ¢ballous dermatitis © Pancreas 580515; artery disease lll periodontitis blood poisoning gingivitis gums; carcinogenesis ¢peripheral artery disease 'metastasis of carcinoma' solid cancer tumors autoimmune autoimmune hepatitis chypobaropathy hypotensive cholangitis “primary biliary cirrhosis SY chepatitis | 0 epartial liver resection partial asl resection ¢sclerosing cholangitis sclerosing alcoholic aS fibrosis ¢cirrhosis cacute liver necrosis acute liver ¢fulminant hepatic failure fulminant hepatic failure chepatic failure gas Ji ccirrhosis ¢late-onset hepatic failure late-onset acute—on-chronic' liver failure 01 selected diseases or disorders to be treated and/or prevention with compounds having the formula heart liver liver kidney from group consisting of refusal to transplant organs such as kidneys (1); vaccination against a host for diseases skin ala cornea pancreas pancreas lung Lung (180; cell transplantation WA graft-versus—host diseases and sclerosing rheumatoid arthritis including rheumatoid arthritis Ly) Autoimmune symptoms 0

Crohn's such as Crohn's disease, inflammatory bowel diseases, comic inflammatory bowel diseases, psoriasis, psoriasis, Ulcerative colitis, and ulcerative colitis6 such as Hashimoto's thyroiditis, psoriatic arthritis, rhinitis aif Jie atopic diseases ala and retinitis-7760n; asthma diseases; Diabetes catopic dermatitis Aa conjunctivitis 000[07011/1015; and inflammation © in which rheumatic fever and glomerulonephritis Loy first type; Post-infectious autoimmune diseases

-1?-

in the post-infection stage; And solid cancers and cancerous tumors.

Particularly favored diseases or disorders are selected that are treated and/or prevented using

A compound of formula (1) from the group formed from the body's rejection of transplanted organs

extracted from kidneys, liver, heart, lungs; vaccination against host diseases caused by stem cell transplantation,

Selected subjective symptoms of rheumatoid arthritis, multiple sclerosis, psoriasis, arthritis

psoriatic; Crohn's disease; Hashimoto's thyroiditis; and atopic dermatitis. It is preferred ha

To select diseases or disorders that can be treated and/or prevented using the compounds that have them

Formula (1) of multiple sclerosis and psoriasis.

The present invention also relates to a method for the prevention or treatment of a disease or disorder mentioned herein comprising 0 administration to a subject of a pharmaceutically effective amount of a compound of formula (!).

also; Formula (a) compounds are useful; In combination with one or more immunomodulators

aid) for the prevention and/or treatment of the diseases and disorders listed herein. According to a preferred model of

the invention Factors are chosen from the group that makes up the immunosuppressive substances

Cimmunosuppressants NSAID's corticosteroids Vo cytotoxic drugs “adhesion molecule inhibitors”

cytokines cytokine inhibitors cytokine receptor antagonists

Cytokine receptor antagonists

.recombinant cytokine receptors

The present invention Lad relates to the use of a compound of formula (1) to prepare a pharmaceutical composition; optionally in the form of Yo for use in combination with one or more immunomodulatory agents; for the prevention or treatment of

Diseases and disorders mentioned here.

Compounds of formula (1) can be synthesized by the methods presented below; by the methods presented in the examples

or by corresponding methods. Hall reaction conditions can vary with the reactants

8015© the specific solvents or solvents used; But these conditions can be determined by Yo the person experienced in this field with routine optimization procedures.

The compounds of formula (a) of the present invention may be prepared according to the general sequence of reactions specified below.

a

-11- which lead to compounds of formula (A). synthetic and have only a few synthetic possibilities

Jie in the solvent 1 Structure By the reaction of the structure compound (I) the compounds of the formula, etc., are prepared at a temperature of “DME” dioxane, THF (DMF pyridine) toluene Jie auxiliaries Room or high temperatures in the presence or absence of auxiliary materials

NaH, etc.); bases (e.g. HCI; acetic acid; TFA; acids (e.g. 0 hydrochloric acid)&("ta-alkylammonium salts Na,CO; K,CO; NE oxalyl) or dehydrating agents (e.g. Oxalyl chloride ctetraalkylammonium salts

POCI;, PCls, “carboxylic acid anhydride” chloride

Lit.: e.g. A.) etc. Burgess Reagent cmolecular sieves Molecular Sieves (P40)

R. Gangloff, J. Litvak, E. J. Shelton, Sperandio, V. R. Wang, K. Na.

Rice, Tetrahedron Lett. 42 (2001), 1441-1443; T. Suzuki, K. Iwaoka, N.

Imanishi, Y. Nagakura, K. Miyta, H. Nakahara, M. Ohta, T. Mase, Chem.

Pharm. Bull. 47 (1999), 120-122; A. F. Poulain, A.L. Tartar, B.P.

Déprez, Tetrahedron Lett. 42 (2001), 1495-1498; M. Srivastava, F.J.

S. Oliveira, No. 5. Machado, R. M. Souto-Maior, Synthetic Commun. 29 0 (1999), 1437-1450; E. O. John, J. M. Shreve, Inorganic Chemistry 27 (1988), 3100-3104; 8. Kaboudin, K. Navaee, Heterocycles 60 (2003), (2287-2292 1c = 0

R2

HN

1 The structure with the structure compound? In solvent 1 by the reaction of structure compound 1 structure compounds Yo can be prepared

TBTU, DCC, Jie, etc. in the presence of one or more conjugate factors «DMF, THF, DCM such as DIPEA, NaH, K,CO; (Jie etc.) and in the presence or absence of EDC, HBTU, CDI gay

-m1- etc (eg Lit.: e.g.

A.

Hamze, J.-F.

Hernandez, P.

Fulcrand, J.

Martinez, J. Org.

Chem. 68 (2003), 7316-1 and references cited above). R! HO-NH R2 b ave mil Chassis 1 Chassis? © Structure 7 compounds can be prepared by reacting the structure complex of with hydroxylamine or one of its salts in a solvent such as (MeOH, EtOH, pyridine, etc., in the presence or absence of the base Jin, 00a6a, and 1800 potassium tert. butylate potassium tert.butylate « and Alal etc. ‎Lit.: e.g.

E.

Meyer, A.

C.

Joussef, H.

Gallardo, Synthesis) WO 2004/035538 (Merck & Co., Inc., USA ,899-905, 2003)- Cl NC R? coon 0 Chassis ¢ Chassis o Chassis compounds can be prepared ¥ By reacting 2-chloro-isonicotinic acid or a suitable ester derivative thereof (structure 5, where R is eg methyl; ethyl isopropyl etc.) with dialkyl zinc -Zn; alkyl-Zn or article 1 reagent halogen cycloa la, Zn- cycloalkyl Js! for conditions Lit.: e.g. ( Negishi Matsushita, E.

Negishi, J.

Org.

Chem. 47 (1982), 4161-4165) with a suitable alkyl or β Grignard reagent cycloalkyl eg Je cycloalkyl in the presence of Fe(acac), in a solvent such as THF (Derxan DMF 0). /la; etc.; or combinations thereof; at temperatures from VA= to ©C under the conditions Lit.: e.g.

A. 10151081, ( 0151081 A.

Leitner, M.

Mendez, H.

Krause, J.

Am.

Chem.

Soc. 124 (2002), 0 A.

Furstner, A.

Leitner, Angew.

Chem. 114 (2002), 632-13856-13863;

-1- 5) or with a 1-alkenyl derivative 1-alkenyl or a cycloalken—1-yl-boron 1- cycloalken—1- Lit.: e.g. F. Kerins, D. F. O'Shea, J. Org. Chem. 67 (2002), () yl-boron 4968-4971 (according to the terms comparing Lit.: e.g. H. Doucet, Eur. J. Org.) Suzuki (Chem. 2008, 2013-2030). In the case, derivatives are used. 1-alkyl boron to insert 0 carbon frame 0 R' J The next hydrogenation step is required to select the desired alkyl or cycloalkyl group.Finally in the case a pyridine-;-carboxylic acid ester is employed acid ester In the steps described above, ester hydrolysis under basic or acidic reaction conditions provides the desired compound of structure 7. 0 Whenever compounds of formula (I) are obtained in the form of mixtures of the Jie isomers Lala enantiomers can be separated using methods known to an expert in this field; She by formation and separation of diastereomeric salts or HPLC through the “chiral stationary phase” such as 5( a Daicel ChiralPak AD-H (5 pm) column, a Daicel ChiralCel OD-H um) column, a Daicel ChiralCel OD (10 um) column, a Daicel ChiralP ak Yo

IA (5 um) column, a Daicel ChiralPak IB (5 pum) column, a Daicel IC (5 um) column, or a (R,R)-Whelk-01 (5 pm) column; In the presence of chiral eluent A (EtOH) HPLC eluent mixture 50018216 under typical conditions for TFA or an acid such as diethylamine and/or diethylamine NEt; or in the absence of a base such as heptane and eluent 8. (heptane 0

Experimental Part The following examples illustrate the invention but do not in any way limit its scope. Chemical shifts are given (Varian Oxford (MHz) Yo) C-NMR :multiplicities relative to the solvent used; multiplications ppm in parts per million shifts Yo 161m6010m =p triplet = t «doublet Su = d »single - 5 l

1 “broad = br imultiplet multi = m 08016] octal = hep chexet _.la.=hex

Finnigan Navigator with HP (LC-MS) Hz Coupling constants presented in Hz o Zorbax SB-AQ (als 46 X 4.1 column 1100 Binary Pump and DAD min; with 0.04 7 of 1 in water; / min (TFA© .melting point) or by melting point ¢ (Fas4 01 Silica gel) silica gel “Merck” 1 mm x ov X-terra RP18 preparation (column HPLC) and the compounds are purified by of formic acid) or by 7 1.5 water containing AMeCN 7 5 -01 Graduation: um

UVIS-2-1 detector Labomatic MD-80-100 pump (MPLC pump)

MeOH of 7 01 Gradient: Labogel-RP-18-55-100 cake YA X You Column Sin: 0 (MeOH 7 001 in water to abbreviations (as used here) aqueous Jl . aq bovine serum albumin Bovine Serum BSA Methoxycarbonylsulfamoyl Triethylammonium Hydroxide Burgess Reagent sale 1 methoxycarbonylsulfamoyl triethylammonium Burgess reagent hydroxide column chromatography CC carbonyl diimidazole CDI

N,N’—dicyclohexyl cyclohexyl carboxylate NON DCC 0 carbodiimide dichloromethane dichloromethane DCM diethyl- ethyl-diazodicarboxylate gh DEAD diazodicarboxylate

Yo

Hining's base, 11001095 Diethylisopropylamine DIPEA £4. Y yy diethylisopropylamine 1,2—-dimethoxyethane 7-dimethoxyethane 1 DME dimethylformamide DMF dimethylsulfoxide DMSO 1,10 Ferrocene (sad | phenyl glow) 1 Dppf 0 bis (diphenylphosphino)ferrocene ethyl acetate EA

N-(3~ methylaminopropyl)-L-1-ethyl-carbodi [imide yad-?(-1 EDC dimethylaminopropyl)-N'-ethyl-carbodiimide ethyl Et ©. ethanol st) EtOH iron (Ill) acetylacetone-complex (Ill) Fe(acac), hour(s) hour(s) -yl) -"l,'la,l,!1 -Tetramethyl uranium hexafluorophosphate 1-(Losyroxine)-0 HBTU

O-(benzotriazol-1-yl)-N,N,N',N'~tetramethyluronium hexafluorophosphate 1 4-)2- ;-(7-hydroxyethyl)1-piperazineethanesulfonic acid HEPES hydroxyethyl)—1- piperazineethanesulfonic acid 1-hydroxy—-benzotriazole -benzotriazole iscorde-1 HOBt high performance HPLC liquid chromatography 0

Alle LC-HRMS high resolution mass spectrometry Measurement —liquid chromatography LC-MS high resolution mass spectrometry Ref Lit.

Jie Me Yo Acetonitrile MeCN £4. Y

L MeOH Methanol Min min(s) MPLC medium pressure liquid chromatography NaOAc© sodium acetate NEt, triethylamine Y= Lithium-1 NMP - Pyrrolidone 1-methyl-2-pyrrolidone Org Organic PPh Triphenylphosphine .prep 0 preparative .quant quantitative rt room temperature .sat saturated SIP sphingosine 1-phosphate lias 1 oF oF »0-)Li-1-LOZYRTZNB-TH)-Y TBTU 10 7 -tetramethyluronium tetrafluoroborate 2-(1H-benzotriazole-1-yl)-1,2,3,3-tetramethyluronium tetrafluoroborate tertiary TFA li-trifluoroacetic acid acid THF Y.tetrahydrofuran j);s, na TLC thin layer chromatography ais, tr retention time preparation of intermediates J YE ¥= (S))-N = -((1-hydroxycarbamimidoyl)-7-methyl-phenoxy]-7-hydroxy-Yopropyl)-?-hydr Loxy-acetamide N-((S)-3-[2-Ethyl-4—(N- ‎hydroxycarbamidoyl)-6-methyl-phenoxy]-2-hydroxy—propyl)-2- Y .£ 4

S hydroxy-acetamide (I to ice cold solution (Je You) 1:50 Jice—cold in water You mL); 2-ethyl-6-methylaniline (2-ethyl-6-methylaniline (Vo,4) g; 111 mmol) was added and the solution was treated with ice (1590 g) before the NaNO (a VV) solution was added. , 100 mmol) in water (Je Vor) and ice (00) (aa) dropwise and the mixture was stirred at zero s.d. 1 hour. 11:50 (Je Yoo) was added. Stirring is continued at room temperature for VA hours.The mixture is extracted with DOM and the organic extracts are dried via MgSO, and evaporated.The crude product is 485 by CC on silica gel sequentially separated by Heptane: 1:4 EA to provide 7-ethyl Jive T=-phenol-Al2-610 (Z OV an AT) 6-methyl-phenol 01 as cochineal oil LC-MS: tz .01101500 oil = Ham' H NMR (CDCl): 0 7.03-6.95 (m, 2H), 6.80 (t, J = 7.6 Hz, “dad 1H), 4.60 (s, 1H), 2.64 (9, J = 7.6 Hz, 2H), 2.25 (s, 3H), 1.24 ) J = 7.6 (Hz, 3H). mol) and hexamethylene tetraamine 0.7 aa 001 ( hexamethylene tetraamine Vo mol) in 101 acetic acid (mL) and water Y1£) ml) to re-flow. Ally condensate is done using a Dean—a Stark apparatus. Approximately 1,701 mL of condensate was collected. The reaction mixture is cooled to room temperature and water (1,000 mL) is added. The thick solution is filtered and the combined solid is dried at 60 °C under vacuum (01 mbar) to provide ?-ethyl-; -hydroxy-*-methyl-0-benzaldehyde (V4) 3-ethyl-4-hydroxy-5-methyl-benzaldehyde g na %) as orange solid min, [M+1+CH,CN]" = 206.27 ; !11:orange = 0.86 wa LC-MS: (s, 1 H), 7.59 (s, 1 H), 7.57 (s, 1 H), 4.64 (s br, 1) 9.84 for NMR (CDCl3): 3H , Ha 7.5 -/ .(H), 2.71 (9, J="1.5Hz, 2H), 2.34 (s, 3H), 1.30 (t, c) Solution of 7 is stirred -ethyl-;-hydroxy-0 dine-benzaldehyde (5.37 g 77.4 mm YO mol) and hydroxylamine hydrochloride (, ag g mmol) in (de Yo) NMP for 1 hour at 0 m under gay vio radiation

A. K. Chakraborti, ©. ; Continuous cooling W Watt You ) microwave irradiation Diluting the mixture with water yy (Kaur, Tefrahedron 55 (1999) 13265-13268

HCI Y The organic extracts are washed with diethyl ether and extracted twice with saturated aqueous diethyl ether and brine 50006. The extracts are combined with NaHCO; watery solution on organic CC; dried over 18250!; filtering and focusing. The crude product is purified by © - to provide ?-ethyl -; -Hydroxy-0-methyl 1:3 EA Heptane quenching silica gel: ald as a yellow solid 3—ethyl-4-hydroxy—-5-methyl-benzonitrile benzonitrile LC-MS: EA = 0.90 min; 1 NMR (CDCl): L (Z AY g £,A4) pale yellow 1.24 (t, J= 7.6 Hz, 3 H), 2.26 (s, 3 H), 2.63 (q, /- 7.6 Hz, 2 H), 5.19 ((s, 1H), 7.30 (s, 2H 0 d) to a solution of ?-ethyl i= -hydroxy -© -methyl-benzonitrile 3-ethyl-4-hydroxy—5- methyl-benzonitrile (1 pg 716 mmol) in A (THF ml); PPh is added (4.07 g; TE,0 mmol) and (60a)-glycidol (Y, V4) (R)—glycidol mL; VE,0 mmol). The mixture is cooled to zero before DEAD is added in 10,A) toluene mL; TEVO mmol). The mixture, VA sad, was stirred for an hour while heating to room temperature. The solvent is evaporated and the product is purified by CC on silica gel separating sequentially with two heptanes: EA will TV (8)-7-ethyl-* -methyl-; -(oxiran-7-ylmethoxy)benzonitrile-3-(9) 0,A0) ethyl-5-methyl-4—(oxiran—2-ylmethoxy)benzonitrile g AT % (as yellow oil: 7.38 0 LC-MS: tg = 0.96 min, [M+42]" = 259.08; 'H NMR (CDCl5): (s, 1 H), 7.35 (s, 1 H), 4.12-4.19 (m, 1 H ), 3.73-3.80 (m, 1 H), 3.36- 0 (m, 1 H), 2.90-2.96 (m, 1 H), 2.68-2.77 (m, 3 H), 2.34 (s, 3 H ), 3.42 (1.26 (t, /- 7.6 Hz, 3H methrexyl)benzonitrile (2.09 g Jim Y= pe) = (8)-3-ethyl-*-methyl (a) is dissolved and The solution was stirred at (Je Yoo) methanol (AN NH; 7 mmol) in 4 h. The solvent was evaporated to give (5)-;-(?-amino-7-hydroxypropoxy)-dA 1#m for Yo (S)—4-(3-amino-2-hydroxypropoxy)-3—ethyl-5- "-ethyl -#-methylbenzonitrile gay

10 e

LC-MS: tg = 0.66 min, quantity); As a yellow oil: px 1,YY) methylbenzonitrile [M+1]" = 235.11; (m, 1 H), 3.68-3.77 (m, 2 H), 2.59-2.75 (m, 4 H), 2.28 (s, 3 H), 1.58 (s br, 2 H), 1.17 (t, J=7.5Hz, 3H to a solution of (8)-(©0-amino-7-hydroxy_propoxy)-?-ethyl-*-methylbenzonitrile (5© 71.5 g £Y) glycolic acid g 7.1 mmol); 1 9 glycolic acid is added

EDC hydrochloride EDC hydrochloride mmol) and 70.1 cpa 4.71 (1081 mmol); h before VA mmol). The mixture is stirred at room temperature for 09 g (1.17) and the saturated aqueous extracts (EA) are dried and extracted twice with NaHCO; diluted with CC, filtered and concentrated. The crude product is purified by (MgSO, organic trans-combined 0--methyl T= i Y= from methanol to provide (5)-[1-[-(?-cyano-7 A) containing DCM (5) -0-[3-)4-0800-2- dymatisea-phenoxy)-?-hydroxy-propyl]-7-hydroxy ethyl-6-methyl-phenoxy)-2-hydroxy-propyl]-2-hydroxy -acetamide

LC-MS: O = 0.74 min, [M+1]" = 293.10; 'H as yellow oil (7 3 + aa Vv, 7)

NMR (CDCly): l 1.25 (t, J= 7.5 Hz, 3 H), 2.32 (s, 3H), 2.69 (9, J= 0 7.5 Hz, 2 H), 3.48-3.56 (m, 3 H ), 3.70-3.90 (m, 3 H), 4.19 (s, br, 3 H), (71.06 (m, 1 H), 7.36 (s, 1 H), 7.38 (s, 1 H g) to solution (5)-71-1-(?-cyano-7-ethyl-7-methyl-phenoxy)-7-hydroxy-propyl]- mmol) in methanol (00 m) hydroxy TY an 19, 7(7-hydroxy-acetamide mmol) and YE an 4,YY) hydroxylamine hydrochloride amine hydrochloride 0 h. YA mmol). The resulting suspension is agitated at *© m for 11 g; 11,1( NaHCO;

Yo) and the mixture is filtered and the filtrate is concentrated ©71081. The residues are dissolved in water and extracted three times with phase 80 ml). The aqueous phase Yoo (EA and de) are separated, filtered, concentrated and dried to give MGSO, and the combined organic extracts are dried over LEA

LC-MS: tg = 0.51 min, [M+1]" = «(Z AY) Title compound as white solid (h YO 326.13; 'H NMR (D-DMSO): 0 1.17 (t, J 7.4Hz, 3H), 2.24 (s, 3H), gay

-?- J7.4Hz, 2 H), 3.23 (m, 1 H), 3.43 (m, 1 H), 3.67 (m, 2 H), 3.83 ,9( 2.62 (s, 2 H), 3.93 (m, 1 H), 5.27 (s br, 1 H), 5.58 (s br, 1 H), 5.70 (s, 2 H), (s, 1 H), 7.36 (s, 1 H) , 7.67 (m, 1 H), 9.46 (s br, 1H) 1.34 2-Ethylisonicotinic acid 0 The title compound is prepared as the hydrochloride salt in analogy to —Y acid (pentane-?-yl) isonicotinic 2—(pentan-3-yljisonicotinic acid ¢ = wa LC-MS: min, [M+1]" = 152.13;'H NMR (CD;0D): 0 8.68 (d, J= 5.4 Hz, 1 0.22 H), 7.99 (s, 1 H), 7.91 (dd, J; = 5.3 Hz, J,=1.3 Hz, 1 H), 2.98 (q, J = Hz, 2 H), 1.37 (t, J= 7.6 Hz, 3 H 1.6) Vo ?-2-Propylisonicotinic acid The title compound is prepared as the hydrochloride salt in analogy with 7-acid (pentane-?-yl) isonicotinic LC-MS: tz = 0.20 min, [M+1]" = « 2-(pentan-3-yljisonicotinic acid 166.10 meqyl Y—propyl isonicotinic LC- MS: ty :Methyl 2—propylisonicotinate min, [M+1]" = 180.33; '"H NMR (CDCl,): [I 8.67 (d, /- 5.0 Hz, 1 = 0.43 H), 7 .70 (s, 1 H), 7.64 (dd, J; = 5.1 Hz, J, =1.5 Hz, 1 H), 3.95 (s, 3H), 10 (m, 2 H), 1.73-1.84 (m, 2 H), 0.97 (t, /J=7.4 Hz , 3H 2.82-2.87. ]" = 166.09; , Jy =4.9 Hz, /,=1.1 0 8.49 .(Hz, 1 H), 2.99-3.08 (m, 1 H), 1.25 (d, /- 6.9 Hz, 6 H ?-butyl isonicotinic acid 2-Butylisonicotinic acid The title compound is prepared as the hydrochloride salt in analogy to 71-(pentane-7-yl) isonicotinic acid: ‎min, [M+1]" = 180.37; 'H NMR (D;-DMF): [I = 0.32 A LC-MS: (d, J=5.8 Hz, 1H), 8.38 (s, 1H), 8.30 (dd, J =5.8Hz, ,=1.4 + 8.98 Hz, 1 H), 3.28-3.34 (m, 2 H), 1.83-1.93 (m, 2 H), 1.36-1.48 (m, 2 H), gay

For 3H ,2 no 7.3 -/ ,) 0.95. 2-Isobutylisonicotinic acid lig Su a) To a solution of 7-chloroisonicotinic acid (© ++, g; 1? mmol) in toluene INN methylformamide is added di-tert.butyl(fe)acetal 1 v,4) N,N-dimethylformamide di—tert.butylacetal g ¥ Ya, mmol) and the mixture was stirred at 0 m 71 s h. The string is concentrated and filtered and the filtrate is diluted with 8, washed with water, dried via MGSO, filtered and concentrated.The crude product is purified by CC on silica gel sequentially separated: Vio BA to provide tert.butyl-7-chloroisonicotinoid tert .butyl 2—chloroisonicotinate (FF can 101) Y,YY) as colorless oil min, :colourless oil = 0.98 and LC-MS: [M+1+CH,CN]" = 255.31 b) under argon to Tert's solution. Butyl 7-chloroisonicotinoid (YL YT) g 004 mmol) in (Je 50( THE) Fe(acac); )£00 mg; 0.19 mmol) is added followed by 1 ,7 can), 20) NMP millimoles). The mixture is cooled to Vom m before isobutylmagnesium chloride (A) isobutylmagnesium chloride mL of a solution of ? molar in (THF) and the mixture was stirred at Yo—C for 1 hour” and then at room temperature for 1 hour. The reaction was rapidly cooled by the addition of water (de 001) and the mixture was extracted with EA The organic extract is dried via MGSO, filtered and concentrated. The crude product CC. is purified on silica gel sequentially separated by heptane: GEA: 1 to present tert. BI-71 0 isobutyl isonicotinate cane 170 ( tert. butyl 2—isobutylisonicotinate 77 4 ) as pale ji oil: 236.39 = LC-MS: tz = 0.82 min, [M+1]" c) The tert mixture is stirred. Butyl 7-isobutyl isonicotinic 1710 (mg; 7.14 mmol) in aqueous Yo 1017 (Je 01) at 10 C for yo h. The mixture is concentrated and dried via high vacuum to give the title compound (1460 mg; qt) as HCl LC-MS: tg = 0.47 min, [M+1]" = 180.09; 'H NMR (001:00): [1 8.88 (d, - 5.9 Hz, 1 H), 8.34 (s, Yo H), 8.29 (dd, 4; =5.9 Hz, J, = 1.4 Hz, 1 H), 3.00 (d, J= 7.4 Hz, 2 H), 1 gay ‏

“YA .(2.14-2.24 (m, 1 H), 1.03 (d, J= 6.6 Hz, 6 H) 2-Isopentylisonicotinic acid The title is in symmetry, butyl 2- tert, butyl 7-isobutylisonicotinic adic

LC-MS: tz = 0.88 min, [M+1]" = 250.40; Title compound: LC-MS: tz = 0.58 min, [M+1]" = 194.30 2-(Pentan-3-yl)isonicotinic acid ) methyl 2-0010015001601086 to a 10 A) methyl-7-chloroisonicotinate solution (dppf) Pd ml); (170 mmol) dry dioxane (squirt) is added to red-brown dioxane (mmol) under argon. To this red-brown suspension 7.17 ca 011 mmol; ©,# can 11,1) 3-pentyl zink Joie zinc is added 2007 h. VA is cooled for 001 m. The mixture is stirred at (THE ml for a +0,000 MV) solution

Veo) and washed with (Jo Yoo) EAL water to room temperature; And dilute it with black solution 1 ml). 100 x (; aqueous DCM. and lye extracted four times in HCL Y ml), filtered and concentrated. The crude product MSO is purified, the combined organic extracts are dried via heptane to present methyl EA on silica gel which is sequentially separated by an MPLC gradient by YY (1 0 g) methyl 2—(pentan-3). -yl)isonicotinate “-(pentane-7-yl)isonicotinate -7- contains a small percentage of methyl 7-(pentane) brownish as brownish oil (XY) and this substance is dissolved in LC-. MS: tg = 0.62 min; [M+1]” = 208.30 YA isonicotinate” for 0 time and the mixture is stirred at (Je YO) aqueous 101 of Yo 7 and (Je Yo) THF beige as a solid (1 TV cane £1V) before being concentrated and dried to present the title compound dela

LC-MS: tz = 0.35 min, [M+1]" = 194.28; 'H NMR (CD,0D): [I 8.74 (d, J = 5.2 Hz, 1 H), 7.97 (s, 1 H), 7.96 (d, J= 6.0 Hz, 1 H), 2.74-2.84 (m, 1 +0

H), 1.71-1.91 (m, 4 H), 0.83 (t, /- 7.4 Hz, 6 H gay

—vq— 7-Cyclopentylisonicotinic acid 2-Cyclopentylisonicotinic acid The title compound is prepared with an analogue of 7-(pentane-?-yl)isonicotinic acid.” LC-MS: tr : = 0.42 min, [M+1 ]" = 192.28; H), 1.80-1.94 (m, 4 (H), 1.70-1.79 (m, 2H) © Examples 1 Example (5)-l!-(?-) 7 -egel = -(h -( 7 -ethyl) pyridine-;-yl)-7?-oxadiazole-?-yl)-7-methyl Y= (mS sid -hydroxypropyl)-7-hydroxyacetamide-4-((2-51-3)-11-( 5) (5—(2-ethylpyridin—4-yl)-1,2,4-oxadiazol-3-yl)-6-methyl-phenoxy)-2- 0 hydroxypropyl)-2-hydroxyacetamide

N—"C b A OH

Y= [nS sit carbamimidoyl)-7-methyl a5 a= N)= to a solution of 1-(5)-7-[7-ethyl-;

N-((S)-3-[2-ethyl-4—(N-hydroxy-propyl)-7-hydroxy-acetamide Vo hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy—propyl)-2 -

edc ml); Add 1 °DMF (mmol) in 0.10 mg (Ya) hydroxy—acetamide (YoY) HCI (0.0 mmol) and 1081 mg (YT); 0.10 mmol).. The mixture was stirred at room temperature (Yo sad) min before 2-ethyl-isonicotinic acid (VEY) 8610 00 mg was added; 0117 mmol). The stirring was continued at room temperature for 1 sad hour. The mixture is diluted with ethyl acetate (50 mL) 1 x 10 (and saturated aqueous (Je 01 XY) brine NaHCO; | and washed twice with mL solution). The organic extract is dried through ,10950, filtered and concentrated. Gay units are dissolved

l remaining structural in dioxane (Je A) and the mixture was stirred at 11 °C for one hour. The mixture is concentrated and the crude product is purified by preparative HPLC (75*30 Waters XBridge 10 pm, ID 007 sequentially separated by acetonitrile gradient in water containing 5# of formic acid To present the title compound (;11 mg) as a beige solid LC-MS: A = 0.63 min, [M+1]" = 441.23; '" H NMR (pale beige wali © (CDCl5): L ‎ 8.77 (d, J=5.0 Hz, 1 H), 7.94 (s, 1 H), 7.84-7.88 (m, 3 H), 7.20 (t, HA 5.5 Hz, 1H), 4.18-4.25 (m , 3 H), 3.90 (dd, 4; = 9.5 Hz, J, = 4.5Hz, 1 H), 3.85 (dd, J; = 9.5 Hz, J, = 6.3 Hz, 1 H), 3.79 (ddd, J, = 14.1 Hz, J, = 6.5 Hz, Js = 3.3 Hz, 1 H), 3.72 (s br, 1 H), 3.49-3.58 (m, 1 H), 2.99 (a, J= 7.6 Hz, 2 H), 2.75 (9, J="T7.5 Hz, 2 H), 2.38 (s, 3H), 0 (1.41 (t, J=7.6 Hz, 3H), 1.32 (t, /- 7.5 2 , 3 H Y Ex. (5)-L-(7-(7-ethyl-;-(*-(?-propylpyridine-;FN(Jr;-oxadiazole-?-yl))- 7-methyl-phenoxy)-7-hydroxypropyl)-7-hydroxyacetamide-(2-81)-3)-11-(5) 4-(5—(2-propylpyridin-4-yl)-1,2 ,4—-oxadiazol-3-yl)-6-methyl-phenoxy)--10 2-hydro xypropyl)-2-hydroxyacetamide N—"C b 0 | 2 \ ya

A

Oh

LC-MS: tz = 0.68 min, [M+1]" = 'beige solid' sale 1. Prepared corresponding to Example 455.22; 'H NMR (CDCly): 0 8.77 (d, J = 5.1 Hz , 1 H), 7.93 (s, 1 H), 7.84-7.89 (m, 3 H), 7.20 (t br, J=5.8 Hz, 1 H), 4.18-4.25 (m, 3 H), 0 3.90 (dd, J; = 9.6 Hz, J, = 4.7 Hz, 1 H), 3.85 (dd, 4; = 9.5 Hz, J, = 6.1 Hz, 1 H), 3.79 (dd, J = 14.1 Hz, J , = 6.5 Hz, J; = 3.0 Hz, 1 H), 3.49- 3.58 (m, 1 H), 2.90-2.96 (m, 2 H), 2.75 (4, J=17.5 Hz, 2 H), 2.39 (s, 3

And

H), 1.81-1.91 (m, 2 H), 1.32 (t, J= 7.5 Hz, 3 H), 1.04 (t, /- 7.3 Hz, 3

H); °C NMR (CDCl): L 173.8, 173.7, 168.9, 164.0, 157.4, 150.2, 137.7, 131.7, 131.5, 128.3, 126.6, 122.3, 120.5, 118.7, 74.2, 70.0, 42.3, 62.1 22.8, 16.5, 14.8, 13.9, this example? (5)-1-(7-(7-ichyl-;-)©-(7-isopropylpyridine-;-yl)-0” 7 4-oxadiazole-?-yl)-7-methylphenoxy)-7 -hydroxy_propyl)-7-hydroxyacetamide-2)-3)-181-(5) Ethyl-4-(5-(2-isopropylpyridin-4-yl)-1,2,4-oxadiazol-3-yl )-6- methylphenoxy)-2-hydroxypropyl)-2-hydroxyacetamide a sim ya \ 2 0 A

Oh 11

LC-MS: tz = 0.71 min, [M+1]" = beige solid. 1. Prepared corresponding to Example 455.20; '" H NMR (CDCly): 0 8.75 (d, J = 5.1 Hz, 1 H), 7.93 (s, 1 H), 7.81-7.86 (m, 3 H), 7.37 (t, J = 5.8 Hz, 1 H), 4.16-4.24 (m, 3 H), 3.82-3.92 (m , 2 H), 3.78 (ddd, J; = 14.0 Hz, J, = 6.5 Hz, J; = 3.1 Hz, 1

H), 3.48-3.57 (m, 1 H), 3.22 (hept, J = 7.0 Hz, 1 H), 2.73 (4, J= 7.5 d Hz, 2 H), 2.37 (s, 3 H) , 1.40 (d, J= 6.9 Hz, 6 H), 1.30 (t, /= 7.5 Hz, 3

h); 36 nmr (CDCL): 0 174.0, 173.4, 169.04, 168.99, 157.4, 150.2, 137.7, 131.70, 131.67, 128.4, 126.7, 122.4, 118.9, 118.6, 74.1, 70.1, 62.2, 42.3, 36.5, 22.9, 22.5, 16.5 , 14.8 0 eg; (5)-l-1-(-(7-ethyl-;-)* -(7-butylpyridine = -yl)-1;oY-oxadiazole-?-yl)-7-methylphenoxy)-? (-hydroxypropyl)-7-hydroxyacetamide-4-a-2-81)-3)-11-(5) (5-(2-butylpyridin—4-yl)-1,2,4-oxadiazol-3-yl )-6-methylphenoxy)-2- t4.Y

_— \ as hydroxypropyl)-2-hydroxyacetamide Pe ya \ 2 0 "PN 88 OH prepared in symmetry with example .1 is a beige solid; = LC-MS: tz = 0.75 min, [M+1]" 'H NMR (CDCly): 0 8.77 (d, J = 5.1 Hz, 1 H), 7.93 (s, 1 H), −469.19 (m, 3 H), 7.24 (t br, J= 5.7 Hz, 1 H), 4.18-4.25 (m, 3 H), © 7.82-7.89 (dd, J = 9.6 Hz, Jb = 4.77 Hz, 1 H), 3.85 (dd, J = 9.5 Hz, Jb = 6.1 3.90 Hz, 1 H), 3.79 (ddd, J; = 14.2 Hz, J, = 6.7 Hz, J; = 3.3 Hz, 1 H), -3.49 (m, 1 H), 3.15 (s br, 2 H), 2.91-2.98 (m, 2 H), 2.74 (q, /- 7.5 Hz, 3.57 tH Hj, 2.38 (s, 3H), 1.76 -1.85 (m, 2 H), 1.40-1.50 (m, 2 H), 1.31 (t, 2 Hz, 3 H), 0.99 (t, J = 7.3 Hz, 3 H); ;): 0 174.0, 0 7.5, 126.7, 128.4, 131.5, 131.7, 137.7, 150.3, 157.4, 164.3, 169.0, 173.2, 22.5, 22.9, 31.9, 38.1, 42.3, 62.2, 70.2, 74.1, 118.7, 120.5, 122.4 16.5 , 14.8 , 13.9 Example o 0 (5)-l-(©-(7-ethyl-?; -) © -(7-isopropylpyridine-;-yl)-0; 7 4 - Oxadiazole-?-yl)-7-methylphenoxy)-7-hydroxypropyl)-7-hydroxyacetamide-2)-3)-1-(5) Ethyl-4 -(5-(2-isobutylpyridin-4-yl)-1,2,4-oxadiazol-3-yl)-6- methylphenoxy)-2-hydroxypropyl)-2-hydroxyacetamide b ya \ 7 0 “PN Ye OH 0 prepared in symmetry with example 1. Wax beige = LC-MS: tg = 0.73 min, [M+1]” b

the 469.21; '" H NMR :(Wa000) 0 8.79 (d, J = 5.1 Hz, 1 H), 7.85-7.91 (m, 4

H), 7.14 ) J= 5.6 Hz, 1 H), 4.17-4.26 (m, 3 H), 3.76-3.94 (m, 3 H), 3.61 (s br, 1 H), 3.49-3.58 (m, 1 H), 3.28 (s br, 1 H), 2.82 (d, J= 7.2

Hz, 2 H), 2.75 (4, J = 7.5 Hz, 2 H), 2.39 (s, 3 H), 2.14-2.28 (m, 1 H), 1.32 (t, /- 7.5 Hz, 3 H), 1.00 (d, J/= 6.6 Hz, 6 RLA 'C NMR (CDCl): 0 0 173.9, 173.5, 169.0, 163.4, 157.4, 150.3, 137.7, 131.7, 131.4, 128.4, 126.7, 122.4, 121.2 Example 0 - LC-HRMS: tg = 1.78 min, [M+H]/z = 469.2451, found = 469.2446 6 Example 0 - -oxadiazole-?-yl) 4 oF »1-(Li-(5)-1-(7-(7-eqyl-;-)*-)7-isopentylpyridine-;(5)-11L -)3-)2-81-(7-methylphenoxy)-7'-hydroxypropyl)-7-hydroxyacetamide 4-(5-(2-isopentylpyridin-4-yl)-1,2,4- oxadiazol-3-yl)-6-methylphenoxy)-2-hydroxypropyl)-2-hydroxyacetamide

N—C b 0 | 7 \ 2

A

OH-

LC-MS: tz = 0.92 min, [M+1]" = «slay solid 1. Prepared in symmetry with Example 483.18; 'H NMR (CDCly): 0 8.79 (d, J = 5.1 Hz, 1 H), 7.95 (s, 1 H), 7.86-7.90 (m, 3 H), 7.12 (t, J = 5.8 Hz, 1 H), 4.17-4.26 (m, 3 H), 3.91 (dd, J = 9.5 Hz, y = 4.8 Hz, 1 H), 3.77-3.88 (m, 2 H), 3.53 (m, 1 H), 2.93-2.99 (m, 2 H), 2.76 (a, J= 7.5 Hz, 2 H), 2.40 (s, 3 H), 1.83-1.88 0 (m, 2H), 1.66-1.76 (m, 1 H), 1.33 ) J= 7.5 Hz, 3 H), 1.01 (d, / 6.2

Hz, 6H); °C NMR (CDCly): 0 173.9, 173.4, 169.0, 164.5, 157.5, 150.3,

RP

(Example 14.8 - 7 = E - Example 7 -(pentane-?-yl)-1.7 4-oxadiazole-(?-yl)-1-methyl (Y)-Y)-N=(S)phenoxy)-7-hydroxypropyl)-7-hydroxy acetamide-2)-5)-4-ala-2-81)-3)-l-1-(5)© (pentan-3-yl)—-pyridin-4-yl)-1,2,4-oxadiazol-3 -yl)-6-methylphenoxy)-2- hydroxypropyl)-2-hydroxyacetamide in cm 0 2 \ ya

A

Oh

LC-MS: tg = 0.80 min, [M+1]" = (zu) 1.JE wax prepared in symmetry with 483.27; '" H NMR (CDCl5): 0 8.80 (d, J = 5.1 Hz, 1 H), 7.81-7.90 (m, 4 0

H), 7.45 (t, /=5.8 Hz, 1 H), 4.57 (s br, 2 H), 4.16-4.25 (m, 3 H), 3.82- 3.92 (m, 2 H), 3.78 (ddd, J ; = 14.0 Hz, J, = 6.5 Hz, J; = 3.1 Hz, 1 H), 3.48-3.57 (m, 1 H), 2.68-2.78 (m, 3 H), 2.37 (s, 3 H), 1.74 -1.87 (m, 4

H), 1.30 ) J = 7.5 Hz, 3 H), 0.83 (t, J = 7.4 Hz, 6 H); C NMR (CDCly): for 174.1, 173.4, 169.0, 167.2, 157.4, 150.4, 137.7, 131.7, 10 131.3, 128.4, 126.7, 122.5, 120.5, 118.8, 74.1, 28.2, 51.2, 61.3, 74.1 , 22.9, 16.5, 14.8, 12.1; LC-HRMS: wa = 1.93 min, [M+H]/z = 483.2607, found = 483.2601

A example is pyridine-; -yl)-0” 7 4-oxadiazole -?- dibs 7-5 )- i= Ja Y)-T)-N=(S) 0 (5(-11-(3-)2- yl) -7-methylphenoxy)-?"-hydroxy_propyl)-"-hydroxyacetamide ethyl-4—(5-(2-cyclopentylpyridin-4-yl)-1,2,4-oxadiazol-3-yl)-6 - methylphenoxy)-2-hydroxypropyl)-2-hydroxyacetamide

ah b decisive ya \ 2 | 0 A OH prepared in analogy to Example 1. Solid LC-MS: tz = 0.78 min, [M+1]" = (slay 'H NMR (CDCly): 0 8.78 ( d, J=5.1 Hz, 1 H), 7.96 (s, 1 H), ;481.06 0E (m, 3 H), 7.25-7.32 (m, 1 H), 4.17-4.25 (m, 3 H) , 3.90 (dd, 7.83-7.88 J =9.5Hz, J,=4.5Hz, 1H), 3.85 (dd, J; =9.5 Hz, J, = 6.0 Hz, 1H), (ddd, J ; = 14.3 Hz, J, = 6.8 Hz, J; = 3.3 Hz, 1 H), 3.49-3.58 (m, 1 3.79 Hz, 2 H), 2.38 7.5 solutions H), 3.45 (s br, 2 H), 3.29-3.39 (m, 1 H), 2.74 (q, (s, 3 H), 2.13-2.27 (m, 2 H), 1.71-1.97 (m, 6 H), 1.31 (t , /- 7.5 3 H); °C NMR (CDCl): 0 174.1, 173.1, 169.0, 167.5, 157.4, 150.2, 0 , 70.2 , 74.1 , 118.7 , 119.5 , 122.4 , 126.7 , 128.4 , 131.7 , 131.7 ,137.7 LC-HRMS: tz = 1.90 ;14.8 ,16.5 ,22.9 ,25.9 ,33.6 ,42.3 ,48.0 ,62.2 .min, [M+H]/z = 481.2451, found = 481.2450 M4 Vo 61/5 test to determine GTPIS assay to determine ECs, values ECs) ad han GTPYS binding tests are carried out in well microtiter plates with 11 wells (442587 (Nunc), in a final volume of Yoo µl only; bast Servants of CHO WIA membrane preparations expressing the recombinant human SIP 510 receptor, or the human STP receptor. The 0 test conditions are 01 mM 001 ((Fluka, 54461) HEPES mM Fluka, ) NaCl Lo (71378 mM Calbiochem, ) BSA Loe “(Fluka, 63064) MgCl, 1 (126609 micromolar Fluka, ) DMSO 7 Y,o (Sigma, G-7127) GDP 0 “(41644 picomolar) PS-GTPyS (Amersham Biosciences, SJ1320) and is gay

a

pH 7,4. Test compounds are dissolved, diluted in 7 001 of DMSO and pre-incubated at room temperature Ty sad min in You μl

of the buffer solution of the previous test in a 5-5" cle and after adding µl of PS-GTPYS the test sad was incubated for one hour at

sha© room. The test is terminated by Ji the reaction mixture to a multiscreen plate (Millipore, MAHFCIH60) using cell harvesting sid.

“Packard Biosciences (harvester) Ice-cold dishes are washed with 10 mM of 01 7 01 (Na,HPO,/NaH,PO, ) dried, sealed at the bottom, and after adding Vo μl (6013621 (6013621) MicroScint20 (Packard Biosciences, order#) and seal

.Packard Biosciences from TopCount at the top. The 76-5 membrane bound B0 limiter PS-GTPYS, which induces 50 7 binding agonists, is measured as the maximum maximal auxiliary concentration. The specific binding is determined by subtracting the specific binding from the maximum binding 01 bound to the multi-sieve plate in the presence of cpm and the maximum binding is the amount of binding and the unspecific binding is the amount of binding in the absence of the test adjuvant.

5 The coactivator activities (ECs af) of all representative compounds have been measured and are in the range of 11 to 1.5 nmolar with a mean of 0.7 nm on the SIP receiver (ECs values) are SIP receiver; in the range of 700 and 19506 with an average of 7141 nanomolar. Ancillary activities are shown in the table.

schedule? : instead of av g = N live f

0 Ter

guy

Ela Y,) 340.0 ethyl 1 I on _ on" LY vat, 0 isopropyl |3 uh kah b _ b 1 8 . on" _ : b B 7" 5 0 Cyclopentyl A TE 1 Bag 01 JE Evaluation of efficacy in vivo Evaluation of efficacy of formula (A) daddy compounds is measured by WAN circulating lymphocytes after oral administration of l? to 01 mg/kg 7019/9 of Formula (I) 8 compound for male Wistar rats ©/00111018051. Animals are housed under climate—controlled conditions with day cycle/ Dark VY hours and includes free access to the gale rat chow and drinking water.Blood is collected before and after a and an hour of drug administration.Whole blood is subjected to hematology using a system (Bayer Diagnostics, Inc.). 201160, Switzerland) Advia Hematology Y .£4

m Data are presented as mean +/a58. Statistical analyzes were performed by analysis of variance (ANOVA) using Statistica (StatSoft) and Newman-Keuls -5000601 for multiple comparisons. And the null hypothesis is rejected when (JES ..,.5 > The table shows the effect on lymphocyte counts 7 hours after the oral administration of 10 mg/kg of the compound of the present invention to male Wister rats. normotensive compared to the vector-only group of animals.lymphocyte counts were measured 7 hours after oral administration of L?A among the representative compounds and are in the range of -1 7 to 77 7 with mean JY table;

A

£4. Y

Claims (1)

q — since claimants 0 compound of Formula “Formula (I) 1c > ym ANN R2 on Formula (I) Bis oo any alkyl “C, s— alkyl or cyclopentyl and “—OCH,-CH(OH)-CH,-NHCO-CH,0H represents R? or salt from that. ‎n- Ju gyn ethyl Ji) R! Gua) according to the claim is Al cisobutyl n-butyl lytob-0 cisopropyl isopropyl 0 dsopentyl bent-7-yl Al-0601-3; Or cyclopentyl, or salt thereof. The compound according to claim dus) c “n-propyl Jun dsopropyl isobutyl or cyclopentyl or salt of Ye represents it. 4 The compound of claim 1 where R! is cyclopentyl or a salt thereof. oY. is a compound pursuant to any of claims 1 to ;; where the stereocenter is gay PR in formation ~OCH,-CH(OH)-CH,-NHCO-CH,0OH R? of a stereocenter group of that. salt or a salt of the group consisting of: lide) according to the protection element compound 1? -oxadiazole-?-yl)-7-7 (dr -(e-( 7-ethylpyridine-; = JA 7(5)-l-(?-(©-hydroxypropyl)-7) -Hydroxyacetamide-4-Al (2-81)-3)-11-(5) Y= (mS si-methyl (5-(2-ethylpyridin—4-yl)-1,2,4-oxadiazol- 3-yl)-6-methyl-phenoxy)-2- ¢ hydroxypropyl)-2-hydroxyacetamide == (dr Y= 7-propylpyridine-;-yl)-0,7?-oxadiazole (-©) - = Ji (Y)-Y)-N=(S)methyl-phenoxy)-7-hydroxypropyl)-7-hydroxyacetamide-4-(2-81)-3)-11-(5)Vo (5) -(2-propylpyridin-4-yl)-1,2,4-oxadiazol-3-yl)-6-methyl-phenoxy)-2- ¢ hydroxypropyl)-2-hydroxyacetamide (5)-1-(7-) (7-Igyl-;-(©-(7-isopropylpyridine-;-yl)-1,7,4-oxadiazole-?-(5(-1-)3-)2-yl)-7- methyl-phenoxy)-7-hydroxypropyl)-7-hydroxyacetamide ethyl-4—(5-(2-isopropylpyridin-4-yl)-1,2,4-oxadiazol-3-yl)-6—- 100 ¢ methylphenoxy) -2-hydroxypropyl)-2-hydroxyacetamide? -oxadiazole-?-yl)-7-17 NV (dr(5)-l!-(?-( 7-ethyl = -(e-(7-butylpyridine-;methylphenoxy)-7- Hydroxypropyl)-7-hydroxyacetamide-4-Al (2-81)-3)-11-(5)‎ (5-(2-butylpyridin—4-yl)-1,2,4-oxadiazol-3-yl) -6-methylphenoxy)-2- ¢ hydroxypropyl)-2-hydroxyacetamide 0 pyridine-; -yl)-1, 7, 4-oxadiazole -?- Os sal Y)=0)= (5)-1-(7-(7-ioqyl-;)5(-1-)3- (2-yl)-7-methylphenoxy)-7-hydroxypropyl)-7-hydroxyacetamide ethyl-4—(5-(2-isobutylpyridin-4-yl)-1,2,4-oxadiazol-3-yl (-6-(methylphenoxy)-2-hydroxypropyl)-2-hydroxyacetamide -(e-(7-isopentylpyridine-;-yl)-1,7,4-oxadiazole-?-yl)-£= Ja Y)-7)-N=(S) Yo (7-methylphenoxy)-7-hydroxypropyl)-? - Hydroxyacetamide - except (2-81)-3)-11-(5) gay PR 4-(5-(2-isopentylpyridin-4-yl)-1,2,4-oxadiazol-3-yl)-6- methylphenoxy)-2-hydroxypropyl)-2-hydroxyacetamide; (5). )-7-methylphenoxy)-7-hydroxypropyl)-7-hydroxyacetamide-2)-3)-1-(9) ethyl-4-(5-(2—(pentan-3-yl)-pyridin—4 -yl)-1,2,4-oxadiazol-3-yl)-6—-© methylphenoxy)-2-hydroxypropyl)-2-hydroxyacetamide; and (5)-L-1-(7-(7-ethyl) -;-(5-(7-pentylcyclopyridine-;-yl)-01, 7, ;-oxadiazole-?-yl)-7-methyl_phenoxy)-7-hydroxy_propyl)-7-hydroxyacetamide-2)- 3)-1-(9) ethyl-4—(5-(2-cyclopentylpyridin-4-yl)-1,2,4-oxadiazol-3-yl)-6-¢ methylphenoxy)-2-hydroxypropyl )-2-hydroxyacetamide 0 or the salt of these compounds .compounds LY - the compound of claim 1 which is (5)-1-(3-(7-ethyl-); - (©-(7-pentylcyclopyridine f=-yl)-1, 7, 4-oxadiazole (Ar Y= -7-methylphenoxy)-?- Spm Vopropyl)-7 -hydroxyacetamide-2)-5)-4-a2-1)-3)-11-(5) ‎cyclopentylpyridin—4-yl)-1,2,4-oxadiazol-3-yl)-6-methylphenoxy )-2- hydroxypropyl)-2—-hydroxyacetamide or a salt thereof. A pharmaceutical composition comprising compound 0 according to any of Claims 1 to ov or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. ‏ .carrier A is a compound pursuant to any of claims 1 through 7; Or a pharmaceutically acceptable salt Yo of that” or a pharmaceutical composition according to protection element A for use as a gay medicine and Ve is a compound according to any of claims 1 through 7; Or a pharmaceutically acceptable salt from that »; For use in the prevention or treatment of diseases or disorders associated with the immune system © human immune system compound (ye) pursuant to any of claims 1 through 7; Or a pharmacologically acceptable salt for use in prevention or treatment of diseases, diseases, or disorders selected from the group consisting of 0 refusal to transplant transplanted organs such as kidney kidneys liver Liver heart 06811, lung 9, pancreas 08001685, cornea skin skin 517 grafting diseases caused by stem cell transplantation (5160; autoimmune symptoms Ly including rheumatoid arthritis) “lai yautoimmune syndromes including rheumatoid arthritis, multiple sclerosis,” and inflammatory bowel diseases, such as Crohn’s disease, ulcerative colitis, psoriasis, and psoriatic arthritis se. lal “psoriatic arthritis thyroiditis e.g. Hashimoto's thyroiditis and uveo—© 05; ala atopic diseases e.g. aif 010105 conjunctivitis cconjunctivitis aa Atopic dermatitis 6AM 210; asthma tasthma bitter Z diabetes type 0 first ctype | diabetes post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis 051-17160105; solid cancers and tumor metastasis NY Yo compound according to any of claims 1 to 7; Or a pharmaceutically acceptable salt, from that, for use in prevention from or The basis for treatment is diseases, diseases, or disorders, disorders selected from the group formed by the body's rejection of the transplanted organs, which are selected from kidneys, kidneys, liver, liver, heart (lung 45 heart), vaccination against a host graft-versus—host 5 diseases caused by stem cell transplantation Autoimmune syndromes © selected rheumatoid arthritis, multiple sclerosis psoriasis psoriatic arthritis psoriatic 5 ) 8; Crohn's disease, Hashimoto's thyroiditis, and atopic dermatitis. 0 17 Use of compound according to any of claims 1 to 7-; Or pharmaceutically acceptable salt, oe pharmaceutically acceptable salt; To prepare a pharmaceutical composition for prevention or treatment of diseases or disorders associated with the activated Immune system Vo Y .£4 The validity period of this patent is twenty years from the date of filing the application, provided that the annual financial fee is paid for the patent and that it is not invalid or forfeited for violating any of the provisions of the patent system, layout designs of integrated circuits, plant varieties, and industrial designs, or its executive regulations issued by King Abdulaziz City for Science and Technology; Saudi Patent Office P.O. Box TAT Riyadh 57??11 ¢ Kingdom of Saudi Arabia Email: Patents @kacst.edu.sa